Abstract by Marius Müller

Radiopharmaceuticals have shaped the clinical landscape towards facilitating the design of new drug candidates. They are also heavily used to diagnose or treat a variety of diseases such as cancers or Alzheimer´s disease. Over the years, a broad spectra of radiochemical synthesis methods have been developed to access these radiopharmaceuticals. However, many chemical structures can still not be radiolabeled and more sophisticated, next-generation labeling methods are urgently needed to satisfy the current and future demand for radiopharmaceuticals.

For instance, pretargeted imaging is a new imaging technology that is based on the tetrazine ligation. Respective imaging agents are notoriously difficult to label with fluorine-18 (¹⁸F) and better approaches are required to increase accessibility and radiochemical yields (RCYs) of these structures. In this thesis, such approaches have been developed. The tetrazine ligation can also be used for targeted radioligand strategies. Especially, the combination of this technology with astatine-211 (²¹¹At), one of the best α-emitters for targeted radioligand therapy, is promising and was investigated within this thesis.

The field of radioligand therapy is currently experiencing surging interest. Therefore, it is not surprising that there is a high demand to label various ligands with ²¹¹At. PSMA-targeting vectors for the treatment of late-stage prostate cancer patients with poor prognosis is one of those ligands. Radiochemistry towards more advanced ²¹¹At-labeled small molecule and peptide-based structures is generally challenging.

Together with my coworkers, I refined and developed novel methodologies to overcome such challenges and label and evaluate a set of radioligands, including a ²¹¹At-labeled PSMA targeting vector. A special focus within this thesis was also to develop an extracorporeal trap that would allow to clear PSMA-targeting agents out of the bloodstream via the tetrazine ligation and increase thereby treatment efficacies by improving the therapeutic index. Preliminary results indicate that such clearing might be possible.

A key methodology developed within this Ph.D. thesis is the ²¹¹At-astatination via electrophilic degermylation, amenable to various scaffolds such as highly reactive Tetrazines (Tzs). Intrigued by the properties of organogermanium reagents, I developed a new method to label ¹¹C-aryl nitriles. Electron-rich and electron-neutral (hetero)arenes could be accessed via electrophilic radiocyanation. The methodology proved further amenable towards direct C-H radiocyanation and the radiocyanation of trialkylstannyl derivatives. Moreover, I decided to explore if [¹⁸F]SuFEx or¹⁸F-labeling methods based on boron precursors could be applied to radiolabel Tzs. After an initial optimization, good RCYs could be achieved for both methods. Finally, the in vivo performance of a set of our ¹⁸F-labeled lead Tzs was assessed towards selecting the optimal candidate for pretargeted imaging and future clinical translation. Generally, polar and highly reactive ¹⁸F-labeled Tzs with a net charge of 0 proved superior.

In conclusion, methodologies presented within this PhD project will facilitate the development of various ¹⁸F-, ¹¹C-, and ²¹¹At-labeled radiopharmaceuticals.